Preparation of substituted decenoic acids

ABSTRACT

The invention provides 7-hydroxy-5,8-dioxo-10-phenyldec-9-enoic acid and salts and esters thereof useful as intermediates in the preparation of styryl cyclopentenyl propanoic acids having spasmolytic activity. Also provided is a process for preparing the phenyldec-9-enoic compounds by reaction of 3-oxoheptane-1,7dioic acid with styryl glyoxal.

United States Patent Dawson et al.

[4 1 Sept. 23, 1975 PREPARATION OF SUBSTITUTED DECENOIC ACIDS Inventors: William Dawson, Cfimberley;

Michael John Foulis, Binfield; Norman James Albert Gutteridge, Owlsmoor; Colin William Smith, Bracknell, all of England Lilly Industries, Ltd London, England Filed: Apr. 10, 1974 Appl. No.: 459,830

Assignee:

Foreign Application Priority Data Apr. 12, 1973 United Kingdom 17734/73 US. Cl 260/408; 206/410.9 R; 206/413 Int. Cl. C1 1C 3/02 Field of Search 260/4109 R, 408, 413

[56] References Cited UNITED STATES PATENTS 3,156,714 11/1974 Surmatis 260/4109 R 3,329,694 7/1967 Martel 260/4109 R 3,716,631 2/1973 Steggerder 260/4109 R 3,767,695 10/1973 Pike 260/4109 R Primary Examiner-Patrick P. Garvin Assistant Exiiininer-1ohn F. Niebling Attorney, Agent, or Firm-Steven R. Lammert; James L. Rowe; Everet F. Smith 7 Claims, No Drawings PREPARATION OF SUBSTITUTED DECENOIC- ACIDS This invention relates to the preparation of a novel substituted decenoic acid and derivatives thereof useful in the preparation of pharmacologically active com pounds. 1

According to the present invention, there is provided the novel compound 7-hydroxy-5,8dioxo-lO-phenyldec-9-enoic acid of structure:

(cu -cooa and salts and esters thereof. Preferred salts are the alkali metal salts whilst preferred esters are the C alkyl and halo-C alkyl esters.

The compound of formula I may be prepared in accordance with another aspect of the present invention by reaction of 3-oxoheptane-l ,7-dioic acid with styryl glyoxal, the latter preferably being in the form of its hemihydrate. The reaction is normally carried out in an aqueous medium under acidic or basic conditions. The reaction proceeds smoothly at room temperature and is usually complete within from 12 to 48 hours. The product may be isolated from the reaction medium by evaporation and if desired purified for example by column chromatography.

The resultant compound of formula I is obtained in racemic form due to the presence of an asymmetric centre at the C7-position. If desired, this racemate can be separated into its optical antipodes which form a part of this invention. Separation is accomplished by conventional methods, for example, diastereoisomers may be formed from the racemic mixture by reaction with an optically active amine such as ()ephedrine or and (-)-a-methylbenzylamine, the difference in the solubility of the diastereoisomers obtained permitting selective re-crystallisation of one form and regeneration of the optically active acid of formula I from the mixture.

The salts and esters of the acid of formula l are also formed by conventional means. Thus a salt, either of the racemic or optically active form of the acid, is prepared by reaction with an appropriate base, for example an alkali metal hydroxide, carbonate or hydrogen carbonate. Esters of the racemic or optically active forms of the acid of formula I are prepared by reaction -of the acid with an appropriate esterification agent such as a C, diazoalkane, a C alcohol or C haloalcohol.

As stated above, the compound of formula 1, whether in racemic or optically active form, and salts and esters thereof, are useful as intermediates in the preparation of pharmacologically active compounds. Thus, for example, they may be cyclised by treatment with a base to yield a racemic or optically active styryl eyclopen tenyl propanoic acid of the formula:

or a salt or ester thereof depending onithe starting terial used. The compounds of formula II are useful as spasmolytic agents and they, togetherwith certain related compounds, are more fully described in the speci- EXAMPLE 1 3-Oxoheptane-l,7-dioic acid (1.0 g.) was dissolved in water (5 ml.) and treated with styryl glyoxal hemihydrate (0.97 g.). The mixture was adjusted to pH9 with 1M sodium hydroxide.and stirred for 16 hours, after which it was filtered, the filtrate acidified to pH2 with 1M hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulphate and rotary evaporated to an oil. After purification by chromatography on a silica gel column using chloroform as eluant, 7hydroxy-5,8-dioxo-lO-phenyldec-9-enoic acid, m.p. 99C. (1.33 g.) was obtained as a crystalline solid. The latter, upon treatment with methanol in the presence of p-toluene sulphonic acid, yielded the corresponding methyl ester, m.p. 57C. Similarly, using 2,2,2-trichloroethanol, the corresponding 2,2,2-trichloroethyl ester was obtained.

The starting materials for the foregoing reaction were prepared as follows: 3Oxoheptane- 1 ,7-dioic acid Diethyl 3-oxoheptane-l,7-dioate (23 g.) at 5C. was treated with 5M sodium hydroxide (50 ml.) at a rate such that the temperature did not exceed 10C. After stirring for a further hour, the reaction mixture was stood at 0C. for 24 hours. The solution was acidified (ph2) with concentrated hydrochloric acid (50 ml.) and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulphate and rotary evaporated to an oil. Addition of sufficient ether and petroleum ether (b.p. 60- C.) to the oil to produce turbidity, and cooling to 0C. yielded the desired acid (7.1 1 g.), m.p. 80- 82C. (dee.). Styryl glyoxal hemihydrate Selenium dioxide (427 g. water 140 ml.) and tetrahydrofuran (2.5 l.) were heated to reflux. Benzal acetone (567 g.) was slowly added with stirring and heating to allow gentle refluxing of solution. After three hours the mixture was allowed to cool to room temperature and was kept at this temperature overnight. The mixture was filtered to remove deposited selenium, the filtrate was concentrated by evaporation to a viscous oil and extracted with boiling water 15 l.). The stirred aqueous extract deposited the required compound on cooling. Yield 174 g., m.p. 88 90C.

EXAMPLE 2 7-Hydroxy-5,8-dioxolO-phenyldec-9-enoic acid (0.20 g.) was dissolved in 0.1M sodium hydroxide (17.5 ml.) at room temperature. The solution was stirred for 45 minutes, acidified with 0.1M hydrochlo- 2. The C alkyl or C haloalkyl ester according to claim 1.

3. The sodium or potassium salt according to claim 4. A method of preparing a compound of claim 1, which comprises reacting 3-oxoheptane-l,7-dioic acid with styryl glyoxal to form a racemic mixture of the optically-active isomers of 7-hydroxy-5,8-dioxo-IO-phenyldec-9-enoic acid, and thereafter, optionally:

a. separating the racemic mixture into one or other of the component optically-active isomers by first forming diastereoisomers from the racemic mixture by reaction with an optically active amine, selective recrystallization of one vdiastereoisomeric form, and regeneration of the optically active acid, and/or b. esterifying the 7-hydroxy-5,8-dioxol O-phenyldec- 9-enoic acid with a C diazoalkane, a C alcohol or a C haloalcohol to form a C alkyl or C haloalkyl ester, and/or 0. salifying the acid to form an alkali metal salt.

5. A method according to claim 4, wherein the reaction between the 3-oXoheptane- 1,7-dioi'c acid and the styryl glyoxal is carried out in an aqueous medium.

6. A method according to claim 4, wherein the styryl glyoxal is utilised in the form of its hemihydrate.

7. The compound of. claim 1, said compoundbeing 7-hydroxy-5 ,8'-dioxo-10-pheny1dec 9-enoic acid. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 7HYDROXY-5,8-DIOXO-10-PHENYLDEC-9-ENOIC ACID OF THE FORMULA
 2. The C1-4 alkyl or C1-4 haloalkyl ester according to claim
 3. The sodium or potassium salt according to claim
 1. 4. A method of preparing a compound of claim 1, which comprises reacting 3-oxoheptane-1,7-dioic acid with styryl glyoxal to form a racemic mixture of the optically-active isomers of 7-hydroxy-5, 8-dioxo-10-phenyldec-9-enoic acid, and thereafter, optionally: a. separating the racemic mixture into one or other of the component optically-active isomers by first forming diastereoisomers from the racemic mixture by reaction with an optically active amine, selective recrystallization of one diastereoisomeric form, and regeneration of the optically active acid, and/or b. esterifying the 7-hydroxy-5,8-dioxo-10-phenyldec-9-enoic acid with a C1-4 diazoalkane, a C1-4 alcohol or a C1-4 haloalcohol to form a C1-4 alkyl or C1-4 haloalkyl ester, and/or c. salifying the acid to form an alkali metal salt.
 5. A method according to claim 4, wherein the reaction between the 3-oxoheptane-1,7-dioic acid and the styryl glyoxal is carried out in an aqueous medium.
 6. A method according to claim 4, wherein the styryl glyoxal is utilised in the form of its hemihydrate.
 7. The compound of claim 1, said compound being 7-hydroxy-5,8-dioxo-10-phenyldec-9-enoic acid. 